Hospital acquired bacterial infections are a serious problem due to the emergence of widespread drug resistance. Staphylococcus aureus is the most common Gram positive pathogen isolated from healthcare associated infections (Infection control and hospital Epidemiology, 2008, 29, 996-1011). In India, incidence of drug resistant S. aureus, most commonly MRSA (Methicillin resistant S. aureus, i.e. resistant to B-lactams) can account for 30-50% of isolates from Hospital acquired infections (Journal of Association of Physicians of India, 2010, 58 suppl: 32-6, Journal of Association of Physicians of India, 2010, 58 suppl: 25-31, Journal of Laboratory Physicians, 2010, 2, 82-4). MRSA strains can also be resistant to non-beta lactam antibiotics such as tetracycline and Ciprofloxacin (Journal of Laboratory Physicians, 2010, 2, 82-4, Journal of Korean Medicine, 2011, 26, 604-611). In fact, S. aureus resistant to vancomycin and even newer drugs such as Linezolid have now been reported worldwide (Morbidity and Mortality Weekly Report 2002, 51:565-567, BMC Infectious Diseases 2006, 6, 156-161, J Clin Microbiol 2005, 43, 179-185, JAMA, 2010, 303, 2261-64). Hence, new therapies to treat Staphylococcal infections are urgently needed.
Fatty acid biosynthesis is an essential process that generates precursors for cellular building blocks such as phospholipids, lipoproteins, mycolic acid and cellular components such as the cell envelope. Fatty acid biosynthesis (FAS) can be classified as type 1 and type 2. Type 1 FAS primarily occurs in bacteria and type 2, in eukaryotes. Type 1 FAS involves a cascade of discrete enzymes while type 2 FAS is carried out by a single multifunctional protein. This difference in mechanism makes it possible to develop inhibitors specific for bacteria (Reviewed in Biochem. J. (2010) 430, 1-19).
Synthesis of fatty acids in bacteria occurs by a series of well conserved enzymatic reactions. The last step in the pathway is regulated by enoyl-acyl carrier protein (ACP) reductase (FabI) which is responsible for reduction of the double bond in the enoyl-ACP derivative. In some species such as Pseudomonas, two genes, FabI and FabK, redundantly perform this function, whereas in S. aureus only one gene, FabI is involved (Nature, 2000, 406, 145-146). Gene deletion experiments have shown that FabI is essential for the survival of S. aureus (BMC Genomics 2009, 10, 291-308). In S. aureus and E. coli, this enzyme has been shown to be inhibited by Triclosan and diazaborines (Journal of Antimicrobial Chemotherapy, 2001, 48, 1-6, Journal of General Microbiology, 1992, 138, 2093-100). In addition, Isoniazid, the anti-Tuberculosis drug has been shown to inhibit InhA, the enoyl-ACP reductase homologue from mycobacteria (Reviewed in Accounts of Chemical Research, 2008, 41, 11-20). Further, small molecule inhibitors of FabI have shown anti-Staphylococcal activity (Antimicrobial Agents Chemotherapy, 2009, 53, 3544-8; International Journal of Antimicrobial Agents, 2007, 30, 446-51).
There are no FabI inhibitors currently available for treating Staphylococcal infections. Given the high level of drug resistance and the large unmet clinical need, novel agents to treat S. aureus infections are urgently needed. The present invention provides, in part, compositions with FabI inhibiting properties. The following patents are pertinent to the current invention and constitute prior art: WO 2011/061214A1 and WO 2004/082586A2.